Peripheral leptin regulates bone formation

Abstract

Substantial evidence does not support the prevailing view that leptin, acting through a hypothalamic relay, decreases bone accrual by inhibiting bone formation. To clarify the mechanisms underlying regulation of bone architecture by leptin, we evaluated bone growth and turnover in wild type (WT) mice, leptin receptor-deficient db/db mice, leptin-deficient ob/ob mice and ob/ob mice treated with leptin. We also performed hypothalamic leptin gene therapy to determine the effect of elevated hypothalamic leptin levels on osteoblasts. Finally, to determine the effects of loss of peripheral leptin signaling on bone formation and energy metabolism, we used bone marrow (BM) from WT or db/db donor mice to reconstitute the hematopoietic and mesenchymal stem cell compartments in lethally irradiated WT recipient mice. Decreases in bone growth, osteoblast-lined bone perimeter and bone formation rate were observed in ob/ob mice and greatly increased in ob/ob mice following subcutaneous administration of leptin. Similarly, hypothalamic leptin gene therapy increased osteoblast-lined bone perimeter in ob/ob mice. In spite of normal osteoclast-lined bone perimeter, db/db mice exhibited a mild but generalized osteopetrotic-like (calcified cartilage encased by bone) skeletal phenotype and greatly reduced serum markers of bone turnover. Tracking studies and histology revealed quantitative replacement of BM cells following BM transplantation. WT mice engrafted with db/db BM did not differ in energy homeostasis from untreated WT mice or WT mice engrafted with WT BM. Bone formation in WT mice engrafted with WT BM did not differ from WT mice, whereas bone formation in WT mice engrafted with db/db cells did not differ from the low rates observed in untreated db/db mice. In summary, our results indicate that leptin, acting primarily through peripheral pathways, increases osteoblast number and activity.

Gender- and region-specific alterations in bone metabolism in Scarb1-null female mice

“…Furthermore, gender differences in leptin function in bone development have also been suggested with higher leptin receptor expression in female vs male rats . Moreover, subcutaneous leptin replacement in ob/ob mice resulted in increased trabecular bone area mainly in lumbar vertebra and to a lower extent in femur (Turner et al 2013), which agrees with the bone phenotype of female Scarb1-null mice in which hyperleptinemia is associated with enhanced bone formation in vertebrae and cortical bone; however, work remains to be done to understand why leptinemia is affected in females only.…”

“…As SR-BI was shown to be abundantly expressed in fat tissue (Acton et al 1994), plasma levels of leptin and adiponectine were measured in null mice. Leptin is recognized as an important bone growth modulator (Fleet 2000, Turner et al 2013. Null females showed high plasma levels of leptin under fasting conditions, as leptinemia was normal in Scarb1-null males, suggesting that leptin may explain the gender differences observed in bone status.…”

“…In addition, the adipokine leptin was shown to stimulate SR-BI expression in hepatocytes (Lundasen et al 2003). Sex differences in adipose tissue, the main source of leptin, were documented and recently, leptin has been identified as an important direct bone growth modulator (Turner et al 2013); gender-related differences in regard to effects of leptin on bone were also noted (Thomas et al 2001). Thus, the observed gender differences in the bone structure of Scarb1-null mice may be related to the estrogen, ACTH, and/or leptin hormonal axes.…”

Markers of bone metabolism, serum leptin levels and bone mineral density in preterm babies

“…models with complete deficiency) or if they play an important homeostatic role in the regulation of peak bone acquisition and skeletal remodeling (3). Leptin acts primarily through peripheral pathways and increases osteoblast numbers and activity (4). Studies have shown that leptin levels are lower in preterm newborns.…”

Reduced bone mass accrual in mouse model of repetitive mild traumatic brain injury

“…Furthermore, chemical lesions of neurons in the hypothalamus recapitulated the ob/ob phenotype and abrogated the effect of central leptin administration [22]. In contrast to the inhibitory effects of central leptin on bone formation, other studies have demonstrated an important role for peripheral leptin in stimulating bone formation [e.g., [23][24]. There are other signal systems that may also serve as neural output from the hypothalamus to bone tissues, including the neuropeptide Y and the cannabinoid receptors systems [25].…”